1. Field of the Invention
The present invention relates to a process of N-aminating a series of nitrogen containing heterocyclic compounds. More specifically, the present invention relates to an improved process for the preparation of N-amino-indoles by the N-amination of indoles. This invention also relates to an improved process for the preparation of N-(n-propyl)-N-(3-fluoro-4-pyridinyl)-1H-3-methyl-indol-1-amine and the product derived therefrom.
2. Description of the Prior Art
Various N-amino substituted nitrogen heterocyclic compounds have been used as intermediates in the manufacture of a variety of organic compounds, which are primarily used in pharmaceutical applications among many other uses. A class of nitrogen heterocyclic compounds of particular importance is N-amino indoles. It has been reported in the literature that the N-amination of indoles and other nitrogen heterocycles, such as carbazoles and pyrroles, can typically be performed by the portionwise addition of hydroxylamine-O-sulfonic acid (HOSA) to the indole in the presence of an excess of potassium hydroxide in a solvent such as dimethylformamide (DMF), see for example, Somei, M.; Natsume, M. Tetrahedron Letters 1974, 461. A similar N-amination procedure, for example, of indoles is described in U.S. Pat. No. 5,459,274, both of these references are incorporated herein by reference in their entirety.
However, the above mentioned method has several limitations and is not advantageous for the preparation of several of the N-aminoindoles especially with respect to the large scale and commercial synthesis of N-aminoindoles. For instance, the portionwise addition of the hygroscopic HOSA as a solid poses problems and is not practical. Additionally, the reaction has to be carried out under heterogeneous conditions resulting in unacceptably low yields of the product. Actually, the product yields are typically in the low levels of around 40 percent, and are often variable depending upon the surface area and quality of potassium hydroxide employed and the agitation efficiency of the reaction medium. Thus, this process is not suitable for a scale-up operation. Most importantly, generally, a large excess of the base is used thus necessitating undue waste disposal problems after neutralization and work-up of the product, thus rendering this process uneconomical for a commercial operation.
It has also been disclosed in the literature that N-amination of hexamethyleneimine can be carried out using HOSA in the presence of an aqueous solvent and an inorganic base, see for example EP Patent Application No. 0 249 452, incorporated herein by reference in its entirety. The inorganic bases disclosed therein include hydroxides of alkali metals and hydroxides of alkaline earth metals. Specifically, in this process, it is disclosed that N-amination can be carried out by simultaneous feeding of an aqueous solution of HOSA and an aqueous solution of sodium hydroxide to an aqueous solution of hexamethyleneimine. However, this process is similarly ridden with all of the disadvantages discussed hereinabove and in addition this process is specific to hexamethyleneimine, which is a stronger base than various other nitrogen heterocyclic compounds such as indoles, carbazoles, pyrroles, etc. In spite of this, the reported product yields are very low. Accordingly, there is a need for an improved process for the N-amination of nitrogen containing heterocyclic compounds.
As noted above, the N-amino nitrogen heterocyclic compounds so formed serve as useful intermediates for the formation of N-alkylamino nitrogen containing compounds, for example, N-alkylamino indoles. Generally, N-alkylation of the amino group can be carried out using an alkylating agent such as haloalkane in the presence of a base. However, such alkylation reactions often result in considerable amounts of side products resulting from the competing alkylation of the heterocyclic ring, and therefore, are not desirable, see for example U.S. Pat. No. 5,459,274. In addition, such alkylation processes also generate undue side products such as alkali halides that need to be disposed of rendering them unsuitable for an industrial scale-up operation.
Thus it is an object of this invention to provide a new homogeneous process for the N-amination of a variety of nitrogen heterocyclic compounds.
It is further an object of this invention to provide a process for the N-amination of nitrogen heterocyclic compounds involving an organic base whereby the N-amino-heterocyclic compounds are prepared in high yields and in high purity.
It is also an object of this invention to provide a new N-alkylation process which does not result in any side products thus offering high purity N-alkylamino heterocyclic compounds.
Other objects and further scope of the applicability of the present invention will become apparent from the detailed description to follow.